Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation.
Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation.
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DOI：
10.7150/thno.27868
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Rominger A
中科院分区：
文献类型：
--
作者：
Brendel M;Jaworska A;Overhoff F;Blume T;Probst F;Gildehaus FJ;Bartenstein P;Haass C;Bohrmann B;Herms J;Willem M;Rominger A
β分泌酶（BACE）抑制剂是目前处于临床II/III期试验中的有前景的治疗化合物。临床前[18F]-氟倍他本（FBB）淀粉样蛋白PET成像有助于纵向监测阿尔茨海默病（AD）小鼠模型中的淀粉样变性。因此，我们应用这一治疗诊断学概念，通过连续FBB PET研究新型BACE 1抑制剂在PS2 APP小鼠中的疗效，PS2 APP小鼠的特征在于早期和大量淀粉样蛋白沉积。研究方法：在9.5月龄时，将PS2 APP和C57 BL/6（WT）小鼠分配到治疗（PS2 APP：N=13; WT：N=11）和媒介物对照（PS2 APP：N=13; WT：N=11）组。所有动物都进行了基线PET扫描，并在两个月和四个月治疗期结束后进行了随访扫描。除了通过PET对脑淀粉样变性进行纵向分析外，我们还在最后一次PET检查后进行了生化淀粉样肽定量和组织学淀粉样斑块分析。结果如下：BACE 1受体处理的转基因小鼠在整个处理期间显示额叶皮质淀粉样蛋白信号进展8.4 ± 2.2%，与载体处理的小鼠相比明显更低（15.3 ± 4.4%，p<0.001）。在对照组中增加<3.7%的区域中，进展的完全抑制是明显的，而对照组中增加>10%的区域显示出BACE 1抑制仅40%的衰减。在治疗开始时具有较低淀粉样变性的小鼠中，BACE 1抑制在减弱进展至PET方面显示出更高的功效。治疗小鼠中小斑块的显著减少表明BACE 1对抑制从头淀粉样蛋白生成的主要作用。结论：这项在转基因AD模型中使用BACE 1治疗并结合淀粉样蛋白PET监测的治疗诊断学研究表明，在初始斑块发展较低的区域，淀粉样变性的进展更有效地减少，并揭示了在淀粉样蛋白生成期间需要早期开始治疗。
Beta secretase (BACE) inhibitors are promising therapeutic compounds currently in clinical phase II/III trials. Preclinical [18F]-florbetaben (FBB) amyloid PET imaging facilitates longitudinal monitoring of amyloidosis in Alzheimer's disease (AD) mouse models. Therefore, we applied this theranostic concept to investigate, by serial FBB PET, the efficacy of a novel BACE1 inhibitor in the PS2APP mouse, which is characterized by early and massive amyloid deposition. Methods: PS2APP and C57BL/6 (WT) mice were assigned to treatment (PS2APP: N=13; WT: N=11) and vehicle control (PS2APP: N=13; WT: N=11) groups at the age of 9.5 months. All animals had a baseline PET scan and follow-up scans at two months and after completion of the four-month treatment period. In addition to this longitudinal analysis of cerebral amyloidosis by PET, we undertook biochemical amyloid peptide quantification and histological amyloid plaque analyses after the final PET session. Results: BACE1 inhibitor-treated transgenic mice revealed a progression of the frontal cortical amyloid signal by 8.4 ± 2.2% during the whole treatment period, which was distinctly lower when compared to vehicle-treated mice (15.3 ± 4.4%, p<0.001). A full inhibition of progression was evident in regions with <3.7% of the increase in controls, whereas regions with >10% of the increase in controls showed only 40% attenuation with BACE1 inhibition. BACE1 inhibition in mice with lower amyloidosis at treatment initiation showed a higher efficacy in attenuating progression to PET. A predominant reduction of small plaques in treated mice indicated a main effect of BACE1 on inhibition of de novo amyloidogenesis. Conclusions: This theranostic study with BACE1 treatment in a transgenic AD model together with amyloid PET monitoring indicated that progression of amyloidosis is more effectively reduced in regions with low initial plaque development and revealed the need of an early treatment initiation during amyloidogenesis.